The loss of pVHL leads to von Hippel-Lindau disease, which is characterized by development of tumors that can include renal clear-cell carcinomas (RCCs) and other highly vascularized tumors (Kaelin, Ann Rev Pathol 2:145-173, 2007; Kaelin, Nature Rev Cancer 2:673-682, 2002; and Latif et al., Science 260:1317-1320, 1993). pVHL is the substrate-recognition component of a cullin RING ubiquitin ligase complex also that includes elongin B, elongin C, Rbx1 and Cul2 (Deshaies and Joazeiro, Ann Rev Biochem 78:399-434, 2009; and Kaelin, Nature Rev Cancer 8:865-873, 2008). pVHL's main function as an E3 ligase is to target HIF-1α for degradation during normoxia (Kaelin 2002, supra). The loss of pVHL results in constitutive activation of HIF-1α, which acts as an important transcription factor for target genes such as VEGF, GULT1, CAIX, and HK2 (Gossage et al., Nature Rev Cancer 15:55-64, 2015). As a consequence, HIF-1α induces metabolic adaptation and promotes tumor growth, invasion, migration, metastasis, and angiogenesis through up regulation of its target genes (Gordan and Simon, Curr Opin Genet Devel 17:71-77, 2007; Semenza, Trends Mol Med 7:345-350, 2001; and Semenza, Oncogene 29:625-634, 2010).
pVHL is ubiquitously expressed in normal tissues and cell types (Los et al., Laboratory Investigation; A Journal of Technical Methods and Pathology 75:231-238, 1996). Loss of the VHL gene and germline mutations are important mechanisms of pVHL down regulation in various cancers (Gossage et al., supra), but the regulation of pVHL at the posttranscriptional level remains underexplored. pVHL may be regulated through the ubiquitin—proteasome pathway (Chen et al., Biology of the Cell/Under the Auspices of the European Cell Biology Organization 105:208-218, 2013; Jung et al., Nature Med 12:809-816, 2006; and Pozzebon et al., Proc Natl Acad Sci USA 110:18168-18173 2013), although the identity of pVHL's E3 ligase is not clear.
WD repeat and SOCS box-containing protein 1 (WSB1) has been classified as a substrate recognition subunit of the ECS (ElonginB/CCul2/5-SOCS) ubiquitin ligase complexes (Vasiliauskas et al., Mech Devel 82:79-94, 1999). WSB1 harbors seven WD40 repeats and a SOCS box (Choi et al., J Biol Chem 283:4682-4689, 2008). The expression of WSB1 positively correlates with tumor incidence in cancers such as pancreatic cancer, hepatocellular carcinoma, and salivary gland tumor (Archange et al., PloS One 3:e2475, 2008; Rhodes and Chinnaiyan, Nature Genet 37(Suppl):531-37, 2005; Silva et al., Bioinformatics 27:3300-3305, 2011; and Tong et al., FEBS Lett 587:2530-2535, 2013). WSB1 also is a target of HIF-1 (Tong et al., supra).
The cellular function of WSB1 has not been well studied. WSB1 can mediate homeodomain-interacting protein kinase 2 (HIPK2) ubiquitination, resulting its proteasome degradation (Choi et al., supra). Following DNA damage, WSB1-mediated ubiquitination of HIPK2 is blocked, resulting in HIPK2 stabilization. HIPK2 in turn phosphorylates p53 at Ser46, which is important for activating proapoptotic gene expression (Puca et al., Oncogene 29:4378-4387, 2010). WSB1 overexpression has been shown to promote pancreatic cancer cell proliferation (Archange et al., supra). However, this effect is unlikely due to inactivation of HIPK-p53 pathway, as the pancreatic cancer cell line used in the study contains mutant p53. Thus, WSB1 may promote cancer cell proliferation through other p53-independent mechanisms.